Scott Monnin and his wife, Nora, stalled for five months after the birth of their second daughter in 2013 before testing her for spinal muscular atrophy (SMA), an inherited disease that destroys nerve cells in the spinal cord crucial to muscle activity. Depending on its severity, SMA progressively inhibits one’s ability to stand, walk, or even breathe independently.
Nora had been seven months pregnant with Charlotte, when their firstborn, Margaret, was diagnosed at 20 months after a series of puzzling developmental symptoms. “We waited because we weren’t in an emotional position to be able to accept knowing that a second child had SMA,” Scott Monnin says.
Like many, the Monnins had never heard of the neuromuscular disease before Margaret’s diagnosis, even though it’s the leading genetic cause of death in infants, according to Cure SMA, a patient advocacy group. Its life-shortening potential might be one reason why the disease has not been on the public radar until recently, advocates say. While children like the Monnin daughters developed a less severe form, those with the most damaging type of SMA, called SMA1, will never sit or roll over and will likely die before they reach their second birthday.
Scott recounts his gut-punch reaction when a pediatric neurologist called to share that genetic bloodwork showed that Margaret — or Maggie as she’s known by friends and family — had the disease. “I said, ‘You know, I appreciate you doing what you could,’ ” he recalls telling the physician. “ ‘But you just gave my daughter a death sentence.’ For whatever reason, those words came out of my mouth. I’ve regretted them ever since. But that was my reaction at the time.”
But Maggie and Charlotte, who goes by Charlie, were born on the cusp of an exciting wave of research into the genetic underpinnings of SMA, which is starting to pay off in a series of promising experimental drugs.
The first of them, Spinraza (nusinersen), was approved by Food and Drug Administration (FDA) officials in December 2016. The injectable drug, which continues to be studied in infants and children, uses a novel genetic-targeting approach to help boost the body’s ability to produce more of a protein key to muscle movement. Based on early indications that the drug appears to work better the sooner it’s started, advocates are making their case to state and federal officials that SMA should be added to routine newborn screening.
Federal officials said they approved Spinraza after promising data, including an interim analysis of data in the randomized phase 3 trial involving infant-onset SMA, the most severe form. More recent end-of-study data, presented in April at the American Academy of Neurology meeting, showed continued improvement, with 51 percent of the babies getting the drug reaching motor milestones versus none in the “sham” group who received the mock procedure.
While not all babies respond to Spinraza, the changes in those who do are readily visible, says Richard Finkel, a principal investigator for the study in infants, dubbed ENDEAR.
“They are rolling over, sitting, and continuing to make progress toward standing and bearing weight, [and] improved head control,” says Finkel, chief of the division of neurology at Nemours Children’s Hospital in Orlando, Florida. “They are working toward crawling, and in a couple of cases, even walking.”
A Backup Plan
In patients with SMA, the SMN1 gene is either deleted or mutated, and thus it’s unable to provide the instructions to produce the “survival of motor neuron” (SMN) protein. It’s this protein that helps to maintain the motor nerve cells located in the spinal cord and the brainstem that control muscle movement.
When Maggie was a baby, her physician had remarked on her low muscle tone during checkups, Scott Monnin says. She learned to crawl and stand, but plateaued at the “cruising stage,” holding onto edges of furniture. “She wasn’t able to let go of things,” he says. “She wasn’t taking those experimental steps.”
At least one in 10,000 babies is born with SMA; roughly one in 50 U.S. adults is believed to be a genetic carrier. The disease is recessive, which means that for a child to inherit it, both parents have to carry one defective SMN1 gene.
But it turns out there’s a backup gene, SMN2, which can at least somewhat offset the loss of the missing SMN1 protein. The more copies of the SMN2 gene a child carries — the SMN gene is located in a region of the genome prone to duplication — the less severe the form of SMA. Charlie and Maggie each have three and some people carry as many as five.
The existence of another gene like SMN2 is a rarity, says neurologist John Kissel, who says there is no other disease in humans with a similar genetic backup plan. Roughly speaking, for every copy of the SMN2 gene that an individual carries, 10 percent of the requisite protein is still produced, he says.
“When the spare copy of the gene was discovered, I like to say that was really sexy, in the sense that it was so appealing to investigators,” says Kissel, who chairs the department of neurology and directs the SMA clinic at Ohio State University Wexner Medical Center in Columbus. “Not only [was it] unique, but … it immediately suggested ways to go about treating this.”
Making Sense of Antisense
Since the SMN gene was first identified in 1995, drug development efforts have pursued several tracks, including gene-related targeting and therapies aimed at restoring muscle function or guarding against its progressive loss. (See “Other SMA Targets,” page 34.)
SMN2 isn’t able to produce sufficient quantities of SMN protein because of what’s called a splicing error. In most cases, a gene’s DNA codes for RNA, but the primary RNA molecule has extra segments that do not code for protein. These extra bits (“introns”) are then cut or “spliced out” by the cell. The mature RNA then contains all of the correct bits (“exons”) to instruct the cell to make a fully functional protein. Adrian Krainer, a professor at New York-based Cold Spring Harbor Laboratory and one of the leaders in understanding RNA splicing mechanisms, compares RNA splicing to the old-style process for film production in which “editing, cutting, and pasting” leaves some portions of the film on the cutting room floor.
In the SMN2 gene, the problem is that the seventh exon is skipped by the splicing machinery. This produces a faulty, less functional message. In people with fully functional SMN1 genes, having a wonky SMN2 gene is still okay. In SMA patients, it is not. Spinraza is designed to boost the amount of SMN2 protein. The drug is actually a short RNA molecule that binds near exon 7. By doing so, it is able to instruct the cell not to skip exon 7 and therefore make more potent SMN protein. This approach, where one RNA molecule binds another to alter genetic coding, is called antisense technology.
They are rolling over, sitting, and continuing to make progress toward standing and bearing weight, [and] improved head control. They are working toward crawling, and in a couple of cases, even walking.
To enable Spinraza to reach nerve cells in the spinal cord, it’s injected into the surrounding fluid, in the same way an epidural is administered for pain relief. Krainer is among those who credit the first patients and their families for stepping forward and taking a risk in the hopes of benefitting science if not themselves. “I can’t imagine being the first patient that takes an experimental drug like this, that goes into your spinal cord and brain,” Krainer says. “Their contribution is incredible.”
When Maggie was diagnosed with SMA in late 2012, there weren’t any medications. But Scott and Nora started closely monitoring drug advances, including those by Ionis Pharmaceuticals, which had joined forces with Biogen to develop what would become Spinraza. They were intrigued but had some trepidation. “This is a brand-new drug,” Scott says. “How safe is it really?”
They were more reassured after doing some more digging and communicating with parents whose children were already getting the experimental drug. So when Ionis geared up to launch a randomized phase 3 study for children ages 2 to 12, dubbed CHERISH, Scott and Nora pushed to get their daughters onboard, compiling two thick binders of medical records with photos on the front.
In the end, only Charlie was considered eligible, as Maggie had started walking shortly after her second birthday, making her too advanced to meet the study’s criteria. When Charlie got accepted into the Chicago study site, her parents sat down one night and wondered how they would handle the logistics and costs of the many trips required from their Ohio home nearly five hours away.
But they couldn’t squander this opportunity, Scott says. “If anyone needed to be in [the study], Charlie [needed it more than Maggie],” he says. “She was weaker at the same milestones along the way. We said, ‘We’ve got to give her every shot in the world to catch back up.’”
Since the trial was blinded and randomized, the Monnins would not have known if Charlie received Spinraza from the start. But when federal officials opened up access to all study participants last year in the wake of positive data, the question became moot.
As with the research involving infants, the end-of-study data for CHERISH, also presented at April’s neurology meeting, has proven to be encouraging. Those children taking the drug exhibited a 3.9 average improvement on a motor skills scale after 15 months versus a slight decline averaging 1.o for those children not receiving the drug.
Before Charlie got what her parents suspect was her first Spinraza injection last summer, she could crawl and pull herself up, but she couldn’t stand independently. But shortly before she reached the holidays and her fourth birthday in January 2017, she began standing and taking her first tentative steps. “At this point she can walk approximately 20 feet independently, which is a big deal for us,” Nora says.
We have to be careful not to use the word ‘cure,’ because we don’t know what the sustained effect is.
Charlie and the rest of the young study participants will continue to be monitored by researchers. Another study is looking at how the drug works in infants who carry the SMN1 mutation but haven’t developed symptoms; these are typically siblings of those who have already been diagnosed, says Jill Jarecki, the chief scientific officer for Cure SMA.
The patient advocacy group, which, along with others, has contributed millions of dollars to drug development research, helped launch a coalition early this year to push for routine newborn screening so drugs can be tested in babies before symptoms emerge.
It’s not yet known whether the drug’s cost will put it out of reach for some patients. Biogen priced Spinraza at $125,000 per dose, or as much as $750,000 for the first year and $375,000 in subsequent years, when fewer doses are required.
At press time, some Medicaid programs had committed to covering it. Several commercial insurers — Anthem, Humana — are covering only the most severe form, SMA type 1. Effective April 1, 2017, UnitedHealthcare is covering SMA types 1-3. Discussions with other insurance providers are ongoing, Jarecki says.
Charlie’s drug will be covered through the research trial, but as of early this year the Monnins didn’t yet know if their insurance would pay for Maggie to get Spinraza, which they’re hoping to start as soon as possible.
At this point, there are more questions than answers about the drug’s longer-term potential and risks, says Kissel of Ohio State. Among them: What are the side effects over time? If a child does stabilize or improve, how long should he or she stay on the drug?
And what are the prospects for adults, Kissel asks, who weren’t a part of the research studies and have been living with SMA’s progressive effects for far longer? How long should the medication be tried in those patients? “If, a year and a half later, [the adult patient is] basically the same, are you going to keep giving this very, very expensive drug?”
Finkel is similarly cautious, even with parents whose babies have started the drug before symptoms became visible. “We have to be careful not to use the word ‘cure,’ because we don’t know what the sustained effect is,” he says.
The Monnins say they are realistic, but they relish the view from where they sit these days. Charlie can more easily explore her world, including her preschool classroom; she is able to leave her wheelchair behind more often. “From four years ago until now,” Scott says, “our hope trajectory is completely different.”